US6057294A - Peptide - Google Patents

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US6057294A
US6057294A US08/875,013 US87501397A US6057294A US 6057294 A US6057294 A US 6057294A US 87501397 A US87501397 A US 87501397A US 6057294 A US6057294 A US 6057294A
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peptide
leu
cells
amino acid
amino acids
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Nicholas Manolios
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NORTHERN STONEY AREA HEALTH
Northern Sydney and Central Coast Area Health Services
Novozymes Biopharma DK AS
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Northern Sydney Area Health Service
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
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Definitions

  • the present invention relates to peptides which affect T-cells, presumably by action on the T-cell antigen receptor.
  • the present invention further relates to the therapy of various inflammatory and autoimmune disease states involving the use of these peptides.
  • the peptides are useful in the treatment of disorders where T-cells are involved or recruited.
  • T-cells are a subgroup of cells which together with other immune cell types (polymorphonuclear, eosinophils, basophils, mast cells, B-, NK cells), constitute the cellular component of the immune system. Under physiological conditions T-cells function in immune surveillance and in the elimination of foreign antigen(s). However, under pathological conditions there is compelling evidence that T-cells play a major role in the causation and propagation of disease. In these disorders, breakdown of T-cell immunological tolerance, either central or peripheral, is a fundamental process in the causation of autoimmune disease.
  • Central tolerance involves thymic deletion of self reactive cells (negative selection) and positive selection of T-cells with low affinity for self major histocompatibility complex antigens (MHC).
  • MHC self major histocompatibility complex antigens
  • peripheral T-cell tolerance which are involved in the prevention of tissue specific autoimmune disease. These include: anergy (loss of co-stimulatory signals, down regulation of receptors critical for T-cell activation), deletion of reactive T-cells, ignorance of the antigen by the immune system and suppression of autoreactive T-cells. Tolerance once induced does not necessarily persist indefinitely. A breakdown in any of these mechanisms may lead to autoimmune disease.
  • T-cells Autoimmune disease and other T-cell mediated disorders are characterised by the recruitment of T-cells to sites of inflammation. T-cells at these sites, coupled with their ability to produce and regulate cytokines and influence B-cell function, orchestrate the immune response and shape the final clinical outcome.
  • the critical component of antigen recognition on the surface of T-cells is the complex antigen receptor (TCR) which is a multisubunit structure that recognises antigen in the context of MHC-encoded proteins on the surface of antigen-presenting cells. Disturbance in this intricate structure-function relationship of the TCR, integrating antigen recognition with T-cell activation may provide the therapeutic means to deal with inflammation and T-cell mediated disorders.
  • TCR complex antigen receptor
  • the TCR is composed of at least seven transmembrane proteins.
  • the disulfide-linked ( ⁇ -Ti) heterodimer forms the clonotypic antigen recognition unit, while the invariant chains of CD3, consisting of ⁇ , ⁇ , ⁇ , and ⁇ and ⁇ chains, are responsible for coupling the ligand binding to signalling pathways that result in T-cell activation and the elaboration of the cellular immune responses.
  • CD3 disulfide-linked ( ⁇ -Ti) heterodimer forms the clonotypic antigen recognition unit
  • CD3 the invariant chains of CD3, consisting of ⁇ , ⁇ , ⁇ , and ⁇ and ⁇ chains, are responsible for coupling the ligand binding to signalling pathways that result in T-cell activation and the elaboration of the cellular immune responses.
  • two structural features are common to all known subunits. Firstly, they are transmembrane proteins with a single transmembrane spanning domain--presumably alpha-helical
  • TCR chains have the unusual feature of possessing a charged amino acid within the predicted transmembrane domain.
  • the invariant chains have a single negative charge, conserved between the mouse and human, and the variant chains possess one (TCR- ⁇ ) or two (TCR- ⁇ ) positive charges.
  • TABLE 1 Listed below in TABLE 1 is the transmembrane sequence of TCR- ⁇ in a number of species showing that phylogenetically this region is highly conserved indicating an important functional role. The substitutions between species are very conservative.
  • cDNA complementary strand DNA
  • COS fibroblast line
  • Transmembrane domains are small in size and proteins transversing this region are usually constrained to an alpha-helical configuration.
  • FIG. 1A shows the delayed induction and clinical severity of disease in animals treated or untreated with the core peptide.
  • FIG. 1B shows the average weight of animals treated or untreated with the core peptide.
  • the present inventor has developed a series of peptides that are inhibitors of function of this crucial receptor, presumably by interfering with assembly.
  • the present inventor has also found that these peptides have an effect on T-cell mediated inflammation and that carboxyl terminal conjugation did not alter the function of the peptides. This is exemplified by coupling peptide to a lipid carrier system with increased effect and no loss of function.
  • the present inventor has also found that the peptide alone had the ability to translocate intracellularly making it a potentially effective drug delivery system.
  • the efficacious clinical manifestations of the administered peptide would be a decrease in inflammation, e.g. as demonstrated by a decrease of arthritis in an adjuvant model of arthritis.
  • the present invention consists in a peptide of the following formula:
  • A is absent or 1 or 2 hydrophobic amino acids
  • C is a peptide consisting of 3 to 5 hydrophobic amino acids
  • D is a positively charged amino acid
  • E is absent or up to 8 hydrophobic amino acids
  • C is 3 or 4 hydrophobic amino acids.
  • A is 2 hydrophobic amino acids and E is 1 to 3, and preferably 1, hydrophobic amino acids.
  • B is arginine and D is lysine or B is lysine and D is arginine.
  • the peptide is Gly-Leu-Arg-Ile-Leu-Leu-Leu-Lys-Val (SEQ ID NO: 5), Leu-Lys-Ile-Leu-Leu-Leu-Arg-Val (SEQ ID NO: 6), Gly-Phe-Arg-Ile-Leu-Leu-Leu-Lys-Val (SEQ ID NO: 7) or Phe-Lys-Ile-Leu-Leu-Leu-Arg-Val (SEQ ID NO: 8).
  • the present invention consists in a therapeutic composition comprising the peptide of the first aspect of the present invention and a pharmaceutically acceptable carrier.
  • the present invention consists in a method of treating a subject suffering from a disorder in which T-cells are involved or recruited, the method comprising administering to the subject a therapeutically effective amount of the composition of the second aspect of the present invention.
  • the therapeutic composition may be administered by any appropriate route as will be recognised by those skilled in the art Such routes include oral, transdermal, intranasal, parenteral, intraarticular and intraocular.
  • the present invention consists in a method of delivering a chemical moiety to a cell comprising exposing the cell to the chemical moiety conjugated to the peptide, preferably to the carboxy terminal, as claimed in any one of claims 1 to 10.
  • T-cells A non-exhaustive list of disorders in which T-cells are involved/recruited include:
  • Allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis
  • Autoimmune disease e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, diabetes, Guillain-Barre syndrome,
  • Gastroenterological conditions e.g. Inflammatory bowel disease, Crohn's disease, primary biliary cirrhosis, chronic active hepatitis
  • Infective disease e.g. AIDS virus, herpes simplex/zoster
  • Cardiovascular problems e.g. autoimmune pericarditis
  • Inflammatory conditions e.g. myositis, ankylosing spondylitis.
  • subject is intended to cover both human and non-human animals.
  • the peptide of the present invention is based on a portion of transmembrane domain of TCR- ⁇ .
  • the complete murine sequence of this portion is NLSVMGLRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 9), whereas the corresponding human sequence is NLSVIGFRILLLKVAGFNLLMTL (SEQ ID NO: 4).
  • the peptide includes two positively charged amino acids separated by 3 to 5 hydrophobic amino acids. Further, as will be clear from the following examples, the peptide of the present invention may be modified at the carboxy terminal without loss of activity. Accordingly, it is intended that the present invention includes within its scope peptides which include additional amino acids to the "core" sequence of the peptide of the present invention and which affect the T-cell antigen receptor.
  • the peptide of the present invention is able to enter cells. Accordingly it is envisaged that, apart from its other uses, the peptide of the present invention could be used as a "carrier" to deliver other therapeutic agents to cells. This could be achieved, for example, by conjugating the therapeutic to be delivered into the cell to the peptide of the present invention.
  • hydrophobic amino acids are Ala, Val, Leu, Ile, Pro, Phe, Tyr and Met, whilst positively charged amino acids are Lys, Arg and His.
  • the first step was to synthesise a short hydrophobic peptide corresponding to the predetermined assembly sequence.
  • the amino acid sequence of the competitive peptide is NH 2 -Gly-Leu-Arg-Ile-Leu-Leu-Leu-Lys-Val-OH (SEQ ID NO: 5) hereafter referred to as "core peptide”.
  • core peptide NH 2 -Gly-Leu-Arg-Ile-Leu-Leu-Leu-Lys-Val-OH
  • the core peptide and other peptides listed above were noted to be hydrophobic and insoluble in aqueous solutions.
  • solvents and carriers were tested. These included ethanol, dimethylsulphoxide (DMSO), dimethyl formamide (DMF), trifluoracetic acid (TFA), squalane oil (2,6,10,15,19,23-hexamethyltetracosane), and lipid conjugation by addition of palmitic acid to the core peptide via TRIS-conjugation (Whittaker R.G., Bender V. J. 1991) to increase solubility.
  • the preferred solvent was DMSO and the final concentration used in cell cultures ranged from 0.1%-0.2%. Concentrations of DMSO greater than 1% was toxic to cells.
  • Stock solutions of peptide and lipopeptide conjugates were dissolved in DMSO and used in a 1/1000 dilution.
  • Core peptide containing C 14 -glycine was synthesised by Auspep Australia and used to study solubility.
  • C 14 -peptide dissolved/suspended in DMSO was added to a final concentration of 100 ⁇ M to T-cell media (RPMI 1640 supplemented with 10% foetal calf serum and 0.3% mercaptoethanol: TCM) and shaken.
  • the media was centrifuged and supernatant filtered through 0.2 ⁇ M filter or left unseparated.
  • the total radioactivity in unseparated medium was 20.000 cpm, 1000 cpm after the medium was centrifuged and 500 cpm after the media was filtered.
  • C 14 -peptide was added to a flask of 5 ⁇ 10 6 2B4.11 cells (T-cell hybridoma specific for cytochrome c) in a final concentration of 100 ⁇ M and 0.2% DMSO and incubated overnight.
  • the adherent cells were washed four times with phosphate buffered saline (PBS) in the flask, solubilised with triton-containing buffer and radioactivity counted.
  • PBS phosphate buffered saline
  • Fluoresceinated labelled core peptide was prepared as follows: 10.25 mg of core peptide was dissolved in 0.5 ml dimethylformamide (DMF) and 2 ⁇ M of FITC in 0.5 ml of DMF was added dropwise with stirring, at room temperature. The pH was adjusted to 9 with N-methyl, N,N-diisopropylamine, and the reaction allowed to proceed for 1 hr. Semi-preparative HPLC was then used to separate FITC-peptide from free FITC, using a C-4 column (6 ml/min; buffer A, 0.1% TFA; buffer B, 80% acetonitrile, 20% water; 0.1% TFA; linear gradient of 40%-100% B). Fractions were monitored by analytical HPLC and the fractions containing pure fluoresceinated core peptide (FITC-peptide) pooled.
  • DMF dimethylformamide
  • the purified compounds were evaporated to diyness and lyophilised from tert. butyalcohol to give the fluorescein labelled peptide monopalmitate (R t B , 7.83) and tripalmitate (R t B 9.85) which were tested as described below.
  • TLC of the fluorescein-labelled lipopeptides showed the absence of free FITC and free Gly-Tris-monoparnitate and Gly-Tris-tripalmitate (used in lipopeptide synthesis) (by ninhydrin staining).
  • linkers that can be used to join compounds (such as peptides) with a carboxyl group to an amino group. These include:
  • a linker with an amino group to the compound and a sulphonic acid group to the Tris (or amino acid if present) such as 2-aminoethanesulphonic acid (taurine).
  • Linkers could also contain disulphide groups that would reduce to liberate modified peptide intracellularly.
  • COS cells were grown on coverslips until 80% confluent, washed twice with PBS and incubated with FITC conjugated lipopeptides for 15 min or 2 hr. The final concentration of lipopeptides was 10 ⁇ M and 6.4 ⁇ M for FITC, for each time point respectively. Cells were washed twice with PBS, mounted with PBS/glycerol and examined with confocal microscopy.
  • fluorescein-conjugated lipopeptides can transmigrate across cell membranes and localise to within the cellular cytoplasm, reaching as far as the endoplasmic reticulum (ER), where protein synthesis takes place.
  • ER endoplasmic reticulum
  • the extent of cellular penetration was influenced by the lipid moiety attached to the peptide.
  • the monopaletate had the greater ability to infiltrate within the fibroblasts and T-cells so far examined (see below).
  • the ER is the best site to try and effect assembly. Once all the chains have assembled and transported to the cell surface it may be much harder to disrupt the receptor at the cell surface membrane. Targetting peptides to the ER is an ideal site to disrupt the TCR complex.
  • T-cells were grown in TCM and resuspended in a concentration of 8 ⁇ 10 5 cells/ml. Viability >95% using trypan blue.
  • One ml of cells was added to polypropylene tubes and washed twice with PBS.
  • Cells were resuspended in PBS and one microliter of stock FITC-conjugated lipopeptides added for 30 min. Cells were washed with PBS, mounted with PBS/glycerol, and viewed using confocal microscopy.
  • the T-cell hybridoma 2B4.11 which expresses a complete TCR on the cell surface was used as a positive control to assess the effects of peptides on TCR expression.
  • the cells were grown in TCM.
  • the ⁇ -deficient variant 21.2.2 and the ⁇ - and ⁇ -deficient cell line 3.12.29, derived by repetitive subcloning of 2B4.11 cells (Sussman et al., 1988) and lacking TCR expression were used as negative controls.
  • Peptides tested included core peptide, lipopeptides and a peptide from tumor necrosis factor receptor termed 558 (used as a negative control). The final concentration of each substance used in incubation was 10 ⁇ M.
  • Mouse IgG2a monoclonal antibody (MAb) against TCR- ⁇ chain of the T-cell hybridoma 2B4 (A2B4-2, Samelson et al., 1983), MAb against 2B4.11 TCR- ⁇ chain (K)25), hamster IgG anti-CD3- ⁇ MAb (145-2C11 [2C11], Leo et al., 1987), rabbit anti-CD3- ⁇ polyclonal antiserum raised against purified mouse CD3- ⁇ (127, Minami et al., 1987), anti-CD3- ⁇ polyclonal antibody (R9) raised in goat immunized with a COOH-terminal peptide of the mouse CD3- ⁇ chain (Samelson et al., 1986).
  • FACS analysis 1 ⁇ 10 6 (2B4.11, 21.2.2) cells were incubated with a number of separate peptides and lipopeptides in a final concentration of 10 ⁇ M overnight. The cells were then wvashed with PBS and incubated with 50 ⁇ l primary antibody (A2B4 or 2C11) for 30 mins at 4° C. Cells were washed twice in PBS and 0.1% BSA and incubated for an additional 30 min at 4° C. with FITC-labelled second antibody. Cells were washed two additional times with PBS and 0.1% BSA prior to analysis on a Becton-Dickson FACS Analyser or Becton-Dickson FACS Scan.
  • A2B4 or 2C11 primary antibody
  • An antigen presentation assay (described below) examined the ability of a number of peptides to inhibit T-cell activation following antigen recognition, by measuring the product of T-cell activation, Interleukin-2 (IL-2).
  • IL-2 Interleukin-2
  • the following cell lines were used: 2B4.11, a T-cell hybridoma that expresses a complete antigen receptor on the cell surface (Samelson et al., 1983) and produces IL-2 following antigen recognition (cytochrome c). Interleukin-2 dependent T-cell line (CTLL) for conventional biological IL-2 assays; and the B-cell hybridoma cell line LK 35.2 (LK, I-E k bearing; Kappler et al., 1982) which acts as the antigen presenting cell.
  • CTLL Interleukin-2 dependent T-cell line
  • LK 35.2 LK, I-E k bearing; Kappler et al., 1982
  • the hybridomas were grown in TCM. Cytochrome c (Sigma, USA) was added in the media to give a final concentration of 50 ⁇ M in the antigen presenting assay.
  • T-cell antigen stimulation 2 ⁇ 10 4 LK35.2 cells were co-cultured with 50 ⁇ M pigeon cytochrome c dissolved in PBS and 2 ⁇ 10 4 2B4.11. T-cells for 16 hr. The assay was done in triplicate. Supernatants were recovered and IL-2 content determined by CTLL proliferation. The incorporation of 3 H-thymidine is directly proportional to the amount of IL-2 present in the supernatant. The ability of different peptides to inhibit IL-2 production was examined. In addition to measuring 3 H-thymidine incorporation, IL-2 measurements (IU/ml) were also determined.
  • C 14 -core peptide (5 mg/mouse) was dissolved in 150 microliters of squalane oil and injected at the base of the tail of Balbic mice. After 24 hr, counts were measured from pulped organs. Distribution of the peptide was noted in thymus (5%), spleen (7%), blood (3%) and a large proportion in lymph nodes (28%), kidney (30%) and liver (28%).
  • the rat adjuvant arthritis model is a classic model of inflammation which has been used extensively by a number of laboratories to study disease progression and effects of potential new anti-inflaimatory drugs thereon over the last 30 years (Pearson et al., 1961; Cremer et al., 1990; Holmdahl and Kvick., 1992; Cannon et al.,1993).
  • This model has also been widely used by researchers at the Royal North Shore Hospital over the last 10 years and procedures have been established for the study of this model of inflammation. All procedures on the animals were carried out under halothane/oxygen/nitrous oxide anaesthesia (2% v/v halothane in 1 liter/min O 2 and 2 liters/minN 2 O).
  • Rats were injected intradermally at the base of the tail with a minimal adjuvant dose (1 mg heat killed Mycobacterium tuberculosis [MTB9 in 100 ⁇ l squalane) once and only once.
  • a minimal adjuvant dose (1 mg heat killed Mycobacterium tuberculosis [MTB9 in 100 ⁇ l squalane) once and only once.
  • MTB heat killed Mycobacterium tuberculosis
  • the first experiment consisted of 12 rats weighing approximately 190-210 grams that were purchased from the Perth Animal Resource Centre (ARC) and maintained in the Gore Hill Animal House facility. Used were core peptide (30 mg) suspended in adjuvant (0.6 ml squalane containing 7 mg MTB), core peptide Tris-monopalmitate (15 mg) suspended in 0.6 ml adjuvant, core peptide Tris-tripalmitate 20 mg/0.6 ml of adjuvant.
  • adjuvant 0.6 ml squalane containing 7 mg MTB
  • core peptide Tris-monopalmitate 15 mg
  • core peptide Tris-tripalmitate 20 mg/0.6 ml of adjuvant.
  • Rats were divided into four groups, each group containing three rats. First group received adjuvant only (positive control), second group adjuvant with core peptide, third group core peptide.Tris. monopalmitate suspended in adjuvant, and last group core peptide.Tris. tripalmitate in adjuvant. Rats were injected with the above compounds in a 0.1 ml volume at the base of the tail. Baseline measurements of rat weight, paw width, and tail diameter were made on Day 0, and subsequently on day 4, 7, 9, 14, 16, 18, 21, 25 and 28. Arthritis was graded and animals sacrificed if there was marked swelling, redness and obvious discomfort. Not all rats given MTB developed arthritis. In general more than 80% of control rats developed arthritis.
  • a feature of adjuvant induced arthritis is the development of inflammation in the tail.
  • Tail measurements (mm) between saline injected rats and core peptide treated rats were not statistically significant.
  • Tail diameters from MTB treated rats however were significantly increased (p ⁇ 0.001) compared to saline and core peptide treated rats (p ⁇ 0.001), TABLE
  • MTB alone given to rats caused ulceration and inflammation at the site of injection that was not present with rats given core peptide or saline.
  • Bovine PNM was prepared essentially as described by Norton and Podulso (1973).
  • FIG. 1 A representative example is shown in FIG. 1.
  • core peptide delayed induction and clinical severity of disease Similar data were observed for peptide C.
  • These data confirm the efficacy of core peptide and peptide C as general immunosuppressants.
  • IDDM insulin-dependent diabetes mellitus
  • NOD mouse spontaneous animal models including the NOD mouse
  • a common histopathological feature associated with the development of IDDM is insulitis, the presence within and around the islets of mononuclear cells consisting predominantly of T lymphocytes and to a lesser extent macrophages (Foulis et al., 1986).
  • Experimental strategies aimed at suppressing cellular autoimmunity such as neonatal thymectomy, administration of cyclosporin A or administration of anti-T lymphocyte antibodies prevent the development of diabetes (Campbell et al., 1991).

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US20080200394A1 (en) * 2004-05-27 2008-08-21 Gropep Limited Treatment of Inflammatory Airway Disease
US20090275503A1 (en) * 2005-09-22 2009-11-05 Yeda Research And Developent Co., Ltd. At The Weizman Institute Of Science Diastereomeric peptides for modulating t cell immunity
US20100087380A1 (en) * 2000-05-19 2010-04-08 Alessio Fasano Pharmaceutical compositions for inhibiting intestinal permeability
US20100267651A1 (en) * 1996-06-11 2010-10-21 Nicholas Manolios T cell antigen receptor peptides
WO2018183842A1 (en) 2017-03-31 2018-10-04 The Board Of Trustees Of The Leland Standford Junior University Methods of treating t cell exhaustion by inhibiting or modulating t cell receptor signaling
US10138276B2 (en) 2009-09-30 2018-11-27 Signablok, Inc. Inhibition of TCR signaling with peptide variants
US20190117725A1 (en) * 2009-10-13 2019-04-25 Signablok, Inc. Inhibition of trem receptor signaling with peptide variants
WO2020036987A1 (en) 2018-08-13 2020-02-20 Signablok, Inc. Peptides and compositions for targeted treatment and imaging

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EP0906339A2 (de) * 1996-03-27 1999-04-07 NG, Gordon, Y., K. Antagonisten von rezeptoren und transportmolekülen
AU739130B2 (en) 1996-06-11 2001-10-04 Northern Sydney And Central Coast Area Health Service T cell antigen receptor peptides
US6696545B1 (en) 1997-04-11 2004-02-24 Sangstat Medical Corporation Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation
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EP1870420A1 (de) 2006-06-23 2007-12-26 Max-Delbrück-Centrum Für Molekulare Medizin Peptide, die die Oberflächenexpression des T Zellrezeptor regulieren
WO2010057275A1 (en) * 2008-11-24 2010-05-27 Sydney West Area Health Services Cyclic peptides and uses thereof

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Cited By (11)

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US20100267651A1 (en) * 1996-06-11 2010-10-21 Nicholas Manolios T cell antigen receptor peptides
US20100087380A1 (en) * 2000-05-19 2010-04-08 Alessio Fasano Pharmaceutical compositions for inhibiting intestinal permeability
US20080200394A1 (en) * 2004-05-27 2008-08-21 Gropep Limited Treatment of Inflammatory Airway Disease
US7795223B2 (en) 2004-05-27 2010-09-14 Novozymes Biopharma Au Ltd. Treatment of inflammatory airway disease
US20090275503A1 (en) * 2005-09-22 2009-11-05 Yeda Research And Developent Co., Ltd. At The Weizman Institute Of Science Diastereomeric peptides for modulating t cell immunity
US10138276B2 (en) 2009-09-30 2018-11-27 Signablok, Inc. Inhibition of TCR signaling with peptide variants
US10538558B2 (en) 2009-09-30 2020-01-21 Signablok, Inc Inhibition of TCR signaling with peptide variants
US20190117725A1 (en) * 2009-10-13 2019-04-25 Signablok, Inc. Inhibition of trem receptor signaling with peptide variants
US11638739B2 (en) * 2009-10-13 2023-05-02 Signablok, Inc. Inhibition of TREM receptor signaling with peptide variants
WO2018183842A1 (en) 2017-03-31 2018-10-04 The Board Of Trustees Of The Leland Standford Junior University Methods of treating t cell exhaustion by inhibiting or modulating t cell receptor signaling
WO2020036987A1 (en) 2018-08-13 2020-02-20 Signablok, Inc. Peptides and compositions for targeted treatment and imaging

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